The objective of Project 1 is to address the idea that glial inflammatory changes with over-expression of glia-derived cytokines, in particular interleukin-1 (IL-1) and S100beta, are primer movers in a cascade of events that lead to neuronal cell injury and death in the early pathogenesis of Alzheimer's disease (AD). These cytokine-driven cascades of neuronal dysfunctions include early over-expression of betaAPP, accumulation of neurofibrillary tangles, overgrowth of betaAPP- over-expressing neurites, appearance of neuropil threads, and eventually cell death. Chronic activation of these cytokine-drive neurodegenerative cascades can in turn promote further over-expression of IL-1. In this way these cytokine-driven cascades may become self-propagating as illustrated in the "cytokine cycle". To elucidate aspects of this cycle, we will use molecular techniques to: 1) Define the relationship of glial inflammation to neuronal cell injury (as evidenced by betaAPP over- expression and neurofibrillary tangle formation in neurons, neurites and in neuropil threads, as well as by synaptic changes) and neuronal cell death (as evidenced by TUNEL positivity) in Alzheimer's disease. These will be correlated with the incidence of: i) associated activated microglial over-expression IL-i); ii) associated activated microglia over-expressing IL-1; ii) associated activated astrocytes over- expressing S100beta; iii) associated beta-amyloid plaques of different types; and iv) stages of neurofibrillary tangle formation. 2) Define the temporal and spatial relationships of glial inflammation to neuronal cell injury and death in conditions predisposing to Alzheimer's disease or to accelerated Alzheimer-type senile changes. For this we will use material from patients with Braak and Braak stages of I-IV of Alzheimer- related changes, with Down's syndrome, with head injury, and with epilepsy. 3) Examine the extent and nature of altered glial cytokine expression and of neuronal cell injury and death in genetic animal models with altered expression of cytokine cycle elements. These include betaAPP transgenic mice and S100beta transgenic mice. 4) Assess the local and remote effects of exogenous glial cytokines in vivo, using intracerebral implants of timed-release pellets containing specific glial cytokines and other cytokine cycle molecules. Successful completion of these specific aims will provide information regarding the progression of neuropathological changes and highlight targets for therapeutic strategies to slow the clinical progression of Alzheimer's disease.